九孔鲍和近江牡蛎泛素酶（UBE2D和UIP5）的分子生物学和功能研究
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摘要
贝类是我国海水养殖业的支柱之一,其中双壳贝类牡蛎和单壳贝类鲍是主要的经济贝类品种。然而,随着养殖产量的增加,养殖规模的扩大,养殖海区环境污染日益严重,病害发生日益频繁,使得贝类养殖遭遇重大损失。泛素化修饰属于蛋白质翻译后修饰,在细胞的各种生命活动进程如细胞周期、信号转导、转录调节、DNA修复、细胞凋亡等中发挥着至关重要的作用。为了探索泛素化修饰在贝类免疫反应及抵御不良环境中的作用与机制,为贝类病害防治提供理论基础,本研究克隆并鉴定了九孔鲍泛素偶联酶UBE2D (Ab-UBE2D)和近江牡蛎泛素连接酶UIP5(Ca-UIP5),利用现代生物信息学分析手段,结合分子生物学、免疫学、细胞生物学等技术,对贝类泛素—蛋白酶体系统的这两种相关基因的结构和功能进行了研究。
一、九孔鲍泛素偶联酶UBE2D鉴定及功能研究
从LPS刺激后的九孔鲍血淋巴细胞cDNA文库中获取了Ab-UBE2D的全长序列,并进行了分析和鉴定。鲍UBE2D cDNA全长1005bp,包含一个编码147个氨基酸的完整阅读框。编码蛋白含有一个特征性的UBCc催化支架结构域、一个保守的Cys激活位点和21个泛素—盐硫键反应残基,其氨基酸序列与酵母UBC4/5、人UBE2D1-4等基因的编码氨基酸相似度在80%左右。系统进化分析显示,Ab-UBE2D与酵母UBC4/5和人UBE2D等聚为一支,远离其他类型的泛素偶联酶。组织表达分布研究表明：Ab-UBE2D在检测的各个组织中都有表达,在血淋巴细胞、消化腺和鳃中表达量高于其他组织。同时,LPS和Poly I:C刺激均可诱导Ab-UBE2D基因表达水平显著上升,说明Ab-UBE2D具有广泛的生物学功能,在免疫反应中具有积极作用。为了进一步研究Ab-UBE2D的生物学功能,表达和纯化了Ab-UBE2D蛋白,并利用质谱技术进行了鉴定。细胞免疫荧光显示,Ab-UBE2D主要分布在血淋巴细胞的细胞质中。另外,体外泛素化检测分析表明：Ab-UBE2D可以形成通过硫酯键连接的泛素—偶联酶复合物,即具有泛素偶联酶活性,并且这种活性依赖于ATP供能,表明了泛素化修饰在软体动物鲍中的保守性。
二、近江牡蛎UIP5的鉴定及功能研究
从LPS刺激后的近江牡蛎血淋巴细胞cDNA文库中获取了Ca-UIP5全长序列,并进行了分析和鉴定,这是软体动物中UIP5基因的首次报道。牡蛎UIP5cDNA全长1831bp,包含一个编码549个氨基酸的完整阅读框。编码蛋白的中部和后部分别含有一个由74个氨基酸残基组成的U-box保守结构域和一个39个氨基酸残基组成的RING结构域。进一步分析发现,Ca-UIP5编码蛋白与其他模式动物同源物的全长氨基酸序列相似度在22%-29%,保守结构域相似度在41%-50%。系统进化分析显示,Ca-UIP5与人和斑马鱼的同源物聚在一起,与紫海胆和果蝇的同源物距离相对较远。组织表达分布研究表明：Ca-UIP5在各组织中都有表达,在消化腺、血淋巴细胞和鳃中表达量高于其他组织。同时LPS刺激可诱导Ca-UIP5基因表达水平显著上升,说明Ca-UIP5可能直接或间接地参与了机体的各种生物学过程,在免疫反应中具有积极作用。为了进一步研究Ca-UIP5的生物学功能,表达和纯化了Ca-UIP5保守结构域Ca-UD蛋白,并利用质谱技术进行了鉴定。荧光免疫组化显示,外套膜和性腺中Ca-UIP5蛋白主要分布于细胞核以及部分细胞膜上,消化腺中的阳性信号则主要集中在腺细胞的细胞之中,暗示了Ca-UIP5生物学功能及作用机制的多样性。另外,体外泛素化检测发现Ca-UD在有ATP供能的条件下,可以发生泛素化修饰,即具有泛素连接酶活性,表明了泛素化修饰在软体动物牡蛎中的保守性。由于Ca-UD仅为Ca-UIP5的保守结构域部分,这说明Ca-UIP5的连接酶活性是由U-box保守结构域行使的,其C末端RING结构域缺失并不影响其连接酶的功能。
最后,进行了Ab-UBE2D介导的Ca-UD体外泛素化检测,结果发现Ab-UBE2D可以介导Ca-UD泛素化反应的发生,进一步说明了泛素化修饰在贝类不同物种间的保守性。
Shellfish is one of the leading aquatic products in China, among which, oysters and abalone are the main economic species. However, shellfish farming suffered a great loss due to diseases and environmental pollution with the increasing output and expanded breeding scale. The ubiquitination, which belongs to the protein post-translational modification, plays a critical role in the life process of cells, such as cell cycle, signal transduction, transcriptional regulation, DNA repair, and cell apoptosis and so on. In order to explore the function and mechanism of ubiquitination in shellfish immune response and resisting adverse environment, ubiquitin-conjugating enzyme UBE2D (Ab-UBE2D) in abalone (Haliotis diversicolor) and ubiquitin ligase UIP5(Ca-UIP5) in oyster (Crassostrea ariakensis) have been cloned. Furthermore, functional analyses of these two enzymes of ubiquitin proteasome system have been carried out by bioinformatics methods, molecular biotechnology, immunology technology, cell biology and so on.
1. Identification and Function Study on ubiquitin-conjugating enzyme Ab-UBE2D in abalone
Acquired from the abalone (H. diversicolor) hemocyte cDNA library after LPS stimulation, Ab-UBE2D full-length sequences were analyzed and indentified. The length of UBE2D cDNA is1005bp, including a complete open reading frame encoding147amino acids. Encoded protein contains a characteristic UBCc catalytic stent domain and a conservative Cys residue. The similarity of its amino acid sequence with that of yeast UBC4/5, human UBE2D1-4is about80%. Phylogenetic analysis showed that the Ab-UBE2D is clustered in the same group with the H. sapiens UBE2D1-4enzymes and yeast UBC4. Tissue distribution research showed that Ab-UBE2D is expressed in all the tissue detected and the expression levels in the hemocyte, digestive glands and gills are higher than that in other tissues. At the same time, Ab-UBE2D gene expression levels were all increased by LPS and Poly I:C stimulation, which indicates that Ab-UBE2D has a positive role in the immune response with a wide range of biological functions. In order to further explore its function, Ab-UBE2D protein was expressed, purified and identified by mass spectrometry. Immunofluorescence showed that Ab-UBE2D mainly distributed in the cytoplasm of hemocytes. In addition, the analysis on vitro ubiquitination detection showed that Ab-UBE2D can form ubiquitin through a thioester bond connection-coupled enzyme complexes which is dependent on ATP-dependent energy, which indicates the conservative modification of ubiquitination in mollusk abalone.
2. Identification and Function Study on ubiquitin ligase Ca-UIP5in oyster
Acquired from the oyster (C. ariakensis) hemocyte cDNA library after LPS stimulation, Ca-UIP5full-length sequences were analyzed and indentified, which is the first report on UIP5genes in mollusk. The full length of UIP5cDNA is1831bp, including a complete ORF encoding549amino acids. The encoded protein contains a U-box conservative structure domain of74amino acid residues and a RING structure domain of39amino acid residues in the central and rear part, respectively. Further analysis found that, the similarity of full-length amino acid sequence in Ca-UIP5coding protein and that in other model animals is between22%and29%, and conservative structure domain similarity is between41%and50%, respectively. System evolutionary tree analysis showed that Ca-UIP5is clustered in the same group with that of human and zebra fish. Tissue distribution research showed that Ca-UIP5can be expressed in all the tissue detected and the expression levels in the hecyte, digestive glands and gills are higher than that in other tissues. At the same time, Ca-UIP5expression levels were all increased by LPS stimulation, which indicates that Ca-UIP5is involved in its biological process directly or indirectly including a positive role in the immune response and involved in its biological process directly or indirectly. To explore further its biological function, the conserved U-box domain of Ca-UIP5was expressed and identified by mass spectrometry. Immunohistochemistry analysis showed that Ca-UIP5protein in sexual glands are mainly distributed in the nucleus and the cell membrane partly while the positive signal are mainly concentrated in the gland cells, which implies that the Ca-UIP5has extensive diversity in biological function and mechanism of diversity. In addition, the analysis on vitro ubiquitination detection showed that Ca-UD can happen the ubiquitin-proteasome modification and is dependent on ATP-dependent, which is the ubiquitin-proteasome enzyme activity, indicating the conservative modification of ubiquitination in mollusk oyster. Due to Ca-UD is only part of Ca-UIP5conservative structure domain, above results explain that Ca-UIP5connection enzyme activity is exercised by U-box conservative structure domain and the lack of C end of RING structure does not affect the connecting function of enzyme.
Finally, the fact of Ab-UBE2D mediated Ca-UD in vitro of the ubiquitin-proteasome detection indicated that Ab-UBE2D can mediated Ca-UD ubiquitination, which further showed the conservative of the ubiquitin-proteasome in different species of shellfish.
一、九孔鲍泛素偶联酶UBE2D鉴定及功能研究
从LPS刺激后的九孔鲍血淋巴细胞cDNA文库中获取了Ab-UBE2D的全长序列,并进行了分析和鉴定。鲍UBE2D cDNA全长1005bp,包含一个编码147个氨基酸的完整阅读框。编码蛋白含有一个特征性的UBCc催化支架结构域、一个保守的Cys激活位点和21个泛素—盐硫键反应残基,其氨基酸序列与酵母UBC4/5、人UBE2D1-4等基因的编码氨基酸相似度在80%左右。系统进化分析显示,Ab-UBE2D与酵母UBC4/5和人UBE2D等聚为一支,远离其他类型的泛素偶联酶。组织表达分布研究表明：Ab-UBE2D在检测的各个组织中都有表达,在血淋巴细胞、消化腺和鳃中表达量高于其他组织。同时,LPS和Poly I:C刺激均可诱导Ab-UBE2D基因表达水平显著上升,说明Ab-UBE2D具有广泛的生物学功能,在免疫反应中具有积极作用。为了进一步研究Ab-UBE2D的生物学功能,表达和纯化了Ab-UBE2D蛋白,并利用质谱技术进行了鉴定。细胞免疫荧光显示,Ab-UBE2D主要分布在血淋巴细胞的细胞质中。另外,体外泛素化检测分析表明：Ab-UBE2D可以形成通过硫酯键连接的泛素—偶联酶复合物,即具有泛素偶联酶活性,并且这种活性依赖于ATP供能,表明了泛素化修饰在软体动物鲍中的保守性。
二、近江牡蛎UIP5的鉴定及功能研究
从LPS刺激后的近江牡蛎血淋巴细胞cDNA文库中获取了Ca-UIP5全长序列,并进行了分析和鉴定,这是软体动物中UIP5基因的首次报道。牡蛎UIP5cDNA全长1831bp,包含一个编码549个氨基酸的完整阅读框。编码蛋白的中部和后部分别含有一个由74个氨基酸残基组成的U-box保守结构域和一个39个氨基酸残基组成的RING结构域。进一步分析发现,Ca-UIP5编码蛋白与其他模式动物同源物的全长氨基酸序列相似度在22%-29%,保守结构域相似度在41%-50%。系统进化分析显示,Ca-UIP5与人和斑马鱼的同源物聚在一起,与紫海胆和果蝇的同源物距离相对较远。组织表达分布研究表明：Ca-UIP5在各组织中都有表达,在消化腺、血淋巴细胞和鳃中表达量高于其他组织。同时LPS刺激可诱导Ca-UIP5基因表达水平显著上升,说明Ca-UIP5可能直接或间接地参与了机体的各种生物学过程,在免疫反应中具有积极作用。为了进一步研究Ca-UIP5的生物学功能,表达和纯化了Ca-UIP5保守结构域Ca-UD蛋白,并利用质谱技术进行了鉴定。荧光免疫组化显示,外套膜和性腺中Ca-UIP5蛋白主要分布于细胞核以及部分细胞膜上,消化腺中的阳性信号则主要集中在腺细胞的细胞之中,暗示了Ca-UIP5生物学功能及作用机制的多样性。另外,体外泛素化检测发现Ca-UD在有ATP供能的条件下,可以发生泛素化修饰,即具有泛素连接酶活性,表明了泛素化修饰在软体动物牡蛎中的保守性。由于Ca-UD仅为Ca-UIP5的保守结构域部分,这说明Ca-UIP5的连接酶活性是由U-box保守结构域行使的,其C末端RING结构域缺失并不影响其连接酶的功能。
最后,进行了Ab-UBE2D介导的Ca-UD体外泛素化检测,结果发现Ab-UBE2D可以介导Ca-UD泛素化反应的发生,进一步说明了泛素化修饰在贝类不同物种间的保守性。
Shellfish is one of the leading aquatic products in China, among which, oysters and abalone are the main economic species. However, shellfish farming suffered a great loss due to diseases and environmental pollution with the increasing output and expanded breeding scale. The ubiquitination, which belongs to the protein post-translational modification, plays a critical role in the life process of cells, such as cell cycle, signal transduction, transcriptional regulation, DNA repair, and cell apoptosis and so on. In order to explore the function and mechanism of ubiquitination in shellfish immune response and resisting adverse environment, ubiquitin-conjugating enzyme UBE2D (Ab-UBE2D) in abalone (Haliotis diversicolor) and ubiquitin ligase UIP5(Ca-UIP5) in oyster (Crassostrea ariakensis) have been cloned. Furthermore, functional analyses of these two enzymes of ubiquitin proteasome system have been carried out by bioinformatics methods, molecular biotechnology, immunology technology, cell biology and so on.
1. Identification and Function Study on ubiquitin-conjugating enzyme Ab-UBE2D in abalone
Acquired from the abalone (H. diversicolor) hemocyte cDNA library after LPS stimulation, Ab-UBE2D full-length sequences were analyzed and indentified. The length of UBE2D cDNA is1005bp, including a complete open reading frame encoding147amino acids. Encoded protein contains a characteristic UBCc catalytic stent domain and a conservative Cys residue. The similarity of its amino acid sequence with that of yeast UBC4/5, human UBE2D1-4is about80%. Phylogenetic analysis showed that the Ab-UBE2D is clustered in the same group with the H. sapiens UBE2D1-4enzymes and yeast UBC4. Tissue distribution research showed that Ab-UBE2D is expressed in all the tissue detected and the expression levels in the hemocyte, digestive glands and gills are higher than that in other tissues. At the same time, Ab-UBE2D gene expression levels were all increased by LPS and Poly I:C stimulation, which indicates that Ab-UBE2D has a positive role in the immune response with a wide range of biological functions. In order to further explore its function, Ab-UBE2D protein was expressed, purified and identified by mass spectrometry. Immunofluorescence showed that Ab-UBE2D mainly distributed in the cytoplasm of hemocytes. In addition, the analysis on vitro ubiquitination detection showed that Ab-UBE2D can form ubiquitin through a thioester bond connection-coupled enzyme complexes which is dependent on ATP-dependent energy, which indicates the conservative modification of ubiquitination in mollusk abalone.
2. Identification and Function Study on ubiquitin ligase Ca-UIP5in oyster
Acquired from the oyster (C. ariakensis) hemocyte cDNA library after LPS stimulation, Ca-UIP5full-length sequences were analyzed and indentified, which is the first report on UIP5genes in mollusk. The full length of UIP5cDNA is1831bp, including a complete ORF encoding549amino acids. The encoded protein contains a U-box conservative structure domain of74amino acid residues and a RING structure domain of39amino acid residues in the central and rear part, respectively. Further analysis found that, the similarity of full-length amino acid sequence in Ca-UIP5coding protein and that in other model animals is between22%and29%, and conservative structure domain similarity is between41%and50%, respectively. System evolutionary tree analysis showed that Ca-UIP5is clustered in the same group with that of human and zebra fish. Tissue distribution research showed that Ca-UIP5can be expressed in all the tissue detected and the expression levels in the hecyte, digestive glands and gills are higher than that in other tissues. At the same time, Ca-UIP5expression levels were all increased by LPS stimulation, which indicates that Ca-UIP5is involved in its biological process directly or indirectly including a positive role in the immune response and involved in its biological process directly or indirectly. To explore further its biological function, the conserved U-box domain of Ca-UIP5was expressed and identified by mass spectrometry. Immunohistochemistry analysis showed that Ca-UIP5protein in sexual glands are mainly distributed in the nucleus and the cell membrane partly while the positive signal are mainly concentrated in the gland cells, which implies that the Ca-UIP5has extensive diversity in biological function and mechanism of diversity. In addition, the analysis on vitro ubiquitination detection showed that Ca-UD can happen the ubiquitin-proteasome modification and is dependent on ATP-dependent, which is the ubiquitin-proteasome enzyme activity, indicating the conservative modification of ubiquitination in mollusk oyster. Due to Ca-UD is only part of Ca-UIP5conservative structure domain, above results explain that Ca-UIP5connection enzyme activity is exercised by U-box conservative structure domain and the lack of C end of RING structure does not affect the connecting function of enzyme.
Finally, the fact of Ab-UBE2D mediated Ca-UD in vitro of the ubiquitin-proteasome detection indicated that Ab-UBE2D can mediated Ca-UD ubiquitination, which further showed the conservative of the ubiquitin-proteasome in different species of shellfish.
引文
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